Skip to content

Dr James Sleigh our Scientific Research Correspondent reports on two small, observational studies of the effects of nusinersen in patients with later-onset SMA have recently been published, both of which describe clinically meaningful improvements caused by the treatment:

The first, published in the journal Muscle & Nerve¹, examined the effects of nusinersen on performance and fatigue in the 6-minute walk test (6MWT). The study included 14 children and adolescents (aged 2-15 years) with either SMA Types 2 (1 patient) or 3 (13 patients). All patients received their first nusinersen treatment as part of a previous phase 1b/2a clinical trial (called CS2, click here for more information), were subsequently enrolled in an extension study of nusinersen (called CS12), and were capable of walking.

The 6MWT assesses how far a person can walk in six minutes along a 25 metre linear course. Nusinersen was recently reported to result in an average improvement of 92 metres in a study of 17 children with SMA Type 3 (click here for more information)². A clinically meaningful improvement in this test is considered to be an increase of 30 metres or more compared to the baseline (i.e. first) test score.

Patients in the 533 day-long CS12 extension study reported in the Muscle & Nerve publication, received four additional doses of nusinersen (12 mg) on days 1, 169, 351 and 533, all of which were given by intrathecal injection (into the spinal fluid). The 6MWT was conducted on several occasions.

The previously reported finding that nusinersen causes a clinically meaningful improvement in 6MWT distance was repeated – there was an improvement of 17 metres at day 253 and 98 metres at day 1050 from baseline in the median average distance walked. Furthermore, the level of fatigue, calculated by subtracting the distance walked in the sixth minute from the distance walked in the first minute, appeared to decrease or stabilise – on average, at day 253 there was a reduction of 0.1% and at day 1050 a reduction of 3.8%. This means that patients were able to maintain similar walking speeds over the duration of the test.

There were, of course, individuals who had better responses than others, and some patients that showed little to no response to treatment. Nevertheless, compared to natural history studies of ambulatory patients with SMA Type 3, who show minimal improvements with age and often a decline in 6MWT scores, this study contributes to the data supporting the positive effects of nusinersen in later-onset SMA.

In the second study, published in the Journal of Neuromuscular Diseases³, 17 patients with SMA Type 3 (aged 18-59 years, median age of 34) were treated with intrathecal injections of nusinersen on day 1, 14, 28 and 63, followed by doses every four months up to day 300. The median disease duration of these patients was 23.8 years (ranging from 6 to 53 years), with median age at disease onset of 12 years (range of 1 to 40 years). Seven patients were dependent on a wheelchair, while 12 were ambulant (i.e. could walk, including one patient only capable of taking a few independent steps). All patients had three (four patients) or four (15 patients) copies of SMN2.

The impact of the drug was then monitored using several different functional tests (e.g. 6MWT and the Revised Upper Limb Module [RULM]), while side effects of treatment were also reported. Patients were assessed at baseline, day 63, 180 and 300.

Several functional assessments did not identify a statistically significant effect of nusinersen (e.g. Hammersmith Functional Motor Scale-Expanded [HFMSE]), but some individuals showed improvement (e.g. 41% of patients in the HFMSE). Nevertheless, patients showed statistically significant improvements in the 6MWT at day 180 and 300, the RULM score at day 300, and peak cough flow at day 180.

In the 6MWT, the average improvement in the 11 ambulant patients was 34 metres, ranging from 24 to 83 metres in seven patients that showed an improvement. One patient showed no effect, while two others showed a non-significant decline.

RULM is a motor assessment of the upper limb function specifically designed for SMA patients. A statistically significant improvement from baseline scores was reported on day 300. Six out of 17 patients (three ambulant and three non-ambulant) showed an improvement of 1-2 score points, while nine patients remained stable, and two non-ambulant patients decreased by -1 to -2 points.

Peak cough flow is a measure of the ability to cough, and was significantly improved from baseline at day 180, but not day 300.

Together, the data generated from the multiple functional tests allow the authors to conclude that nusinersen causes a mild treatment effect in adults with long-standing SMA Type 3 after nusinersen treatment over a 10 month period.

As has been reported previously, administration of nusinersen was generally well tolerated, with no serious adverse events reported. However, four patients reported a total 11 instances (out of 108 total injections in the study) of headaches after injection, while one patient reported fatigue in one instance, and seven suffered from lower back pain. These side effects are thought to be linked to the lumbar puncture procedure rather than nusinersen itself.

Nusinersen is a treatment for SMA, not a cure, and one that appears to have different levels of success in different patients. There is now considerable evidence to indicate that the earlier that nusinersen is administered, the more likely it will have a clinically meaningful impact of disease. Moreover, much of what we know about the effects of nusinersen come from clinical trials with patients with SMA Type 1, which manifests early in childhood.

Studies in late-onset SMA impacting adults, such as the two small observational studies reported on here, are very important to get an understanding of what effect nusinersen has in this older population of patients with SMA.

The short-term reported improvements outlined here may be small and should be interpreted with care, especially given the small sample sizes. Nevertheless, they provide an early indication of the usefulness of nusinersen treatment in late-onset SMA. We know from natural history studies that SMA is a chronic disease that gets progressively worse with time. The data highlighted here indicate that nusinersen may be able to restrict deteriorating function of SMA patients, and, in some cases, perhaps even cause a recovery of some function.

  1. Montes et al. (2019) Nusinersen improves walking distance and reduces fatigues in later-onset spinal muscular atrophyMuscle & Nerve 60: 409-436.
  2. Darras et al. (2019) Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies. Neurology 92: e2492-e2506.
  3. Walter et al. (2019) Safety and treatment effects of nusinersen in longstanding adult 5q-SMA Type 3 – A prospective observational study. Journal of Neuromuscular Diseases (jn press).